Hi Charlotte,

are you talking about a human clinical trials, or animal trials?

For human studies, you may want to look at the transplantation of the injection of neural stem cells from the fetus, for a start.

http://www.nature.com/stemcells/2009/0902/090226/full/stemcells.2009.32.html

However, in general terms, human adult stem cells are considered to be safe(er) than anything resembling the embryonic pluripotent state.

The issue with pluripotent stem cells (Embryonic stem cells or induced pluripotent stem cells) is quite clear: these cells should never be used for transplantation in their undifferentiated state, because they retain the ability to form teratomas. In fact, the ability to form teratomas is one of the standard tests of pluripotency for human ES cells, while in mouse, the most stringent test to date is the tetraploid complementation assay.

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0094730

These can not be performed with human ES/iPSCs.

With regards to clinical trials using cells that are derived by the differentiation of ES cells (ESC, or iPSC derived retinal pigmented epithelium - RPE cells) , one of the main safety concerns is complete elimination of pluripotent stem cells. This is achieved, either through differentiation of all the cells away from pluripotency (though not all cells will become RPE cells) and selection of the cells to be used for transplantation. A second way to eliminate any residual cells that have the ability to form teratomas (by virtue of their pluripotency) is through negative selection of cells using live cell sorting (eg. FACS using TRA1-81). Puripotent stem cell suicide tools are also being developed.

The issue becomes even more complicated with iPS cells, because of random viral integration of reprogramming, the nature of the genes themselves, incomplete transgene silencing, epigenetic memory of the iPS cells, lack of epigenetic control in deriving human iPSCs: all of which lead play their own roles in iPS cells misbehaving in vitro. iPS cell misbehaviour can be highlighted in the work by the fact that cells differentiated from some iPSC lines have the ability to spontaneously revert back to a pluripotent state, and then form teratomas.

Making iPS cells "safe" for transplantation has been a major goal of the field, especially over the past 6 years, and there have been many approaches to a) identify the molecular characteristics of "bad vs good iPSCs", b) control or select "good iPSCs" c) eliminate bad iPS cells etc.

I'm not sure what you have learned about iPS cells, but you should take a good look at Yamanaka's progress from the initial generation of iPS cells in mouse (2006), to Yamanaka's and Jamie Thomson's (separate publications in 2007) work in humans, the elimination of viral factors by many labs (including Sheng Ding), and also the identification of better ways to produce iPS cells that can be reprogrammed.

http://labs.gladstone.ucsf.edu/ding/

There are many excellent researchers working in this space (too many to mention here, but you could look at the work of Shinya Yamanaka, Konrad Hochedlinger, Andra Nagy, Mahendra Rao), and I would encourage you to look at reviews that highlight the problems of the field, approaches to overcoming them (such as the generation of iPSCs with non-viral vectors, proteins, miRNAs, small molecules etc.).

It is important to note that the human clinical trial of human ESCs for RPE transplatation has shown no tumor/teratoma formation to date, and have shown therapeutic improvements thus far.

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2814%2961376-3/abstract

Also, on the note of iPSC safety, the first human clinical trials have also begun in Japan. This means that many of the problems I have outlined above have been dealt with sufficiently enough to show excellent results in animal studies, and that iPS cell derived RPE cells are considered safe enough to trial in humans.

I hope this helps you find the reading you need to go forward.

Regards,

Ioannis

When I was working in Moscow, The team of prof SVET-MOLDAVSKY, ZINZAR and other from the Oncologic center of USSR has reported cases of malignant and benign  tumor growing from syngeneic  fetal digestive organs implanted in living adult Balb mice (see literature; through Pubmed, 60-70ies, american journal and NTJ Academy reports - if you do not find them, I shall seek for the references in my personal library). The mentioned authors registred them as AKATON and AKATOL tumor strains in the Tumor Bank of their Institute. Myself and collaborators have obtained the same results with implantation of fetal small bowel in adult Fischer Rats (implantation site - auricle subcutaneous pouches).. These results were published only in Russian journals, and  were the topic of the PhD thesis of L.V.Naumete in the 80ties. BUT later, in Belgium, I was not able to obtain the same result, i.e. a malignant tumor growth from implants of fetal organs whatever rat or mouse strain was used. We observed only benign teratome formation after implantation of  fetal liver into retroperitoneal space or betwenn neck muscles (see publication in 2013-jan or Febr).

So some factors, remaining unknown to me up to now , do enhance the tumor growth out of fetal organ grafts in vivo, thai is from already determined precusor cells. This phenomen is rare. Nevertheless it suggests a careful attitude especially with implantation of fetal organs containing numerous stem cells at the moment of their collection for transplantation.. It also means that investigation of the conditions enhancing this kind of  transformation are wanted.

Excuse me for the possible nyumerous orphographic mistakes: my vision is a little perturbated now.

Good luck anyway,

V.Coulic

Hello

A few cases have come to light of tumours or excessive tissue growth, however. One of the first people to receive fetal stem cells to treat Parkinson's disease was a 50-year-old US citizen in China. Upon his death in 1991, 23 months after surgery, he was found at autopsy to have a teratoma growing in his brain that contained hairs and cartilage.

A more highly publicised case was in 2009, when an Israeli teenager developed brain and spinal tumours after receiving implants of fetal stem cells in Moscow to treat a rare degenerative condition. And in 2010, a 46-year-old woman developed multiple tumours in her kidney after having her own bone-marrow stem cells injected at a private clinic in an attempt to treat kidney failure.

There have also been at least three cases of people developing leukaemia after receiving stem cells from umbilical cord blood. That is less surprising because ordinary bone marrow transplants – which are a source of blood stem cells – also carry that risk . add, in 2005 the woman in the US has developed a tumour-like growth in her back eight years after a stem cell treatment to cure her paraplegia failed . There have been a handful of cases of stem cell therapies causing growths but this appears to be the first resulting from an approved clinical trial at a Western hospital.

 see more about this news here ( http://www.newscientist.com/ )

Good Luck 

http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1000029

Dear Charlotte,

I would agree with Ioannis Limnios. ESCs and iPSCs are "pre-programmed" to recapitulate embryonic development either in vitro or in vivo. Endogenous adult stem cells on the other hand do not share that particular characteristic. We have tested adult totipotent, pluripotent and germ layer lineage stem cells ad nauseum in animal models and have never seen any type of uncontrolled proliferation and/or differentiation other than the lineages present in the local environment.